Gram-negative bacteria have an outer membrane composed of a lipid bilayer, which is not found in Gram-positive bacteria, and therefore tend to have stronger drug resistance than that of Gram-positive bacteria, in relation to problems associated with drug permeability. In addition, the Gram-negative bacteria are known to have a plurality of drug efflux proteins, which are also known to be involved in the drug resistance (Non Patent Document 1). Lipopolysaccharide (LPS), a main constituent of the outer membrane, is further largely involved as an endotoxin in toxicity.
Among the Gram-negative bacteria, particularly, Pseudomonas aeruginosa is known to have a strong tendency to exhibit intrinsic resistance to various antibacterial drugs. Pseudomonas aeruginosa resides widely in a natural environment or a living environment, but is an attenuated bacterium that usually exhibits no pathogenicity to healthy people. This bacterium, however, is a pathogen that causes serious acute infectious diseases such as sepsis for patients having a serious underlying disease, patients, so-called compromised hosts, who use an immunosuppressant as a result of transplantation or the like, and patients under medical practice such as medical catheterization, tracheal cannulation, or surgical operation. Pseudomonas aeruginosa is therefore a causative bacterium important for opportunistic infectious diseases or nosocomial infectious diseases. In recent years, Pseudomonas aeruginosa that has acquired resistance to carbapenem drugs, quinolone drugs, or aminoglycoside drugs, etc., originally expected to be effective for Pseudomonas aeruginosa has often been clinically isolated in medical settings (Non Patent Document 2). In addition, multidrug-resistant Pseudomonas aeruginosa that has acquired resistance to all of these drugs of three lineages has also been isolated (Non Patent Document 3). Since there are few therapeutic agents useful for infection by multidrug-resistant Pseudomonas aeruginosa, refractory infectious diseases caused thereby are major global issues. Thus, the development of a drug having a novel mechanism of action has been strongly demanded.
UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC) is an enzyme responsible for the synthesis of lipid A (hydrophobic anchor for LPS, a constituent of the outer membrane). Lipid A biosynthesis consists of reactions of 10 stages. LpxC catalysts the second stage of the biosynthesis reactions and dissociates the acetyl group of UDP-3-O-acyl-N-acetylglucosamine (Non Patent Document 4). The lipid A is a component essential for outer membrane formation and is eventually essential for the survival of Gram-negative bacteria (Non Patent Document 5). LpxC is a rate-limiting enzyme important for the process of lipid A biosynthesis and is an enzyme essential for the lipid A biosynthesis. Thus, a drug inhibiting the activity of LpxC is strongly expected to serve as an effective antibacterial agent for Gram-negative bacteria including Pseudomonas aeruginosa, particularly, drug-resistant Pseudomonas aeruginosa because of its mechanism of action different from that of conventional drugs.
Compounds having LpxC inhibitory activity have heretofore been known (Patent Documents 1 to 7).
However, the novel hydroxamic acid derivative or a salt thereof of the present invention having LpxC inhibitory activity, and an antibacterial agent comprising the same have not been known so far.